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      Review of the Literature on Current Changes in the Timing of Pubertal Development and the Incomplete Forms of Early Puberty

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          Abstract

          Puberty is a sensitive period of life characterized by the appearance of secondary sex characteristics which leads to a complete sexual maturation. It physiologically starts between the age of 8 and 13 years in girls and 9 and 14 years in boys. In the last two decades, several studies have showed that start of puberty has moved up to younger ages by 12–18 months, and some of the hypotheses trying to explain this change include the role of nutritional status and obesity and the influence of extrinsic factors such as exposure to endocrine-disrupting chemicals (EDCs), as well. The hypothalamic–hypophysis–gonadal axis develops during embryogenesis, and except for a period of activation immediately after birth, remains suppressed until the onset of pubertal development. At the beginning of puberty, the pulse generator is reactivated, probably due to progressive stimulatory influences on GnRH neurons from glial signals and neurotrasmitters. Kisspeptin and its receptor play a fundamental role in this phase. Premature Pubarche/Adrenarche, Premature Thelarche, and Premature Menarche are incomplete forms of precocious pubertal development that have their origin in endocrine mechanisms that only recently have started to be understood. It is important to distinguish these forms from the complete ones in order to reassure patients and parents about the non-evolution of pubertal progression and avoid non-useful treatments with analogous LHRH.

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          Most cited references54

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          Parent-of-origin specific allelic associations among 106 genomic loci for age at menarche

          Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality 1 . Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation 2,3 , but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P<5×10−8) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1/WDR25, MKRN3/MAGEL2 and KCNK9) demonstrating parent-of-origin specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signaling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
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            Examination of US puberty-timing data from 1940 to 1994 for secular trends: panel findings.

            Whether children, especially girls, are entering and progressing through puberty earlier today than in the mid-1900s has been debated. Secular trend analysis, based on available data, is limited by data comparability among studies in different populations, in different periods of time, and using different methods. As a result, conclusions from data comparisons have not been consistent. An expert panel was asked to evaluate the weight of evidence for whether the data, collected from 1940 to 1994, are sufficient to suggest or establish a secular trend in the timing of puberty markers in US boys or girls. A majority of the panelists agreed that data are sufficient to suggest a trend toward an earlier breast development onset and menarche in girls but not for other female pubertal markers. A minority of panelists concluded that the current data on girls' puberty timing for any marker are insufficient. Almost all panelists concluded, on the basis of few studies and reliability issues of some male puberty markers, that current data for boys are insufficient to evaluate secular trends in male pubertal development. The panel agreed that altered puberty timing should be considered an adverse effect, although the magnitude of change considered adverse was not assessed. The panel recommended (1) additional analyses of existing puberty-timing data to examine secular trends and trends in the temporal sequence of pubertal events; (2) the development of biomarkers for pubertal timing and methods to discriminate fat versus breast tissue, and (3) establishment of cohorts to examine pubertal markers longitudinally within the same individuals.
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              Thelarche, pubarche, and menarche attainment in children with normal and elevated body mass index.

              The early onset of puberty may be related to obesity, so there is a need to know the prevalence of early pubertal milestones in nonoverweight children. OBJECTIVE. We compared attainment of stage 2 breasts, stage 3 (sexual) pubic hair, and menarche in the Third National Health and Nutrition Examination Survey sample of children with normal BMI with those with excessive BMI (> or =85th percentile). The ages at which 5%, 50%, and 95% of youth had attained key pubertal stages were estimated by probit models. Logit models were then fit to compare attainment of these milestones in children of excessive and normal BMI. Pubertal signs occurred before 8.0 years of age in <5% of the normal-BMI general and non-Hispanic white female population. However, pubertal milestones generally appeared earlier in normal-BMI non-Hispanic black and Mexican American girls; thelarche occurred before age 8.0 in 12% to 19% of these groups, and the 5th percentile for menarche was 0.8 years earlier for non-Hispanic black than non-Hispanic white subjects. Pubarche was found in < or =3% of 8.0-year-old girls with normal BMI of all of these ethnic groups but was significantly earlier in minority groups. Pubarche appeared before 10.0 years in <2% of normal-BMI boys. Girls with excessive BMI had a significantly higher prevalence of breast appearance from ages 8.0 through 9.6 years and pubarche from ages 8.0 through 10.2 years than those with normal BMI. Menarche was also significantly more likely to occur in preteen girls with an elevated BMI. Prevalence estimates are given for the key pubertal milestones in children with normal BMI. Breast and sexual pubic hair development are premature before 8 years of age in girls with normal BMI in the general population. Adiposity and non-Hispanic black and Mexican American ethnicity are independently associated with earlier pubertal development in girls.
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                Author and article information

                Contributors
                Journal
                Front Pediatr
                Front Pediatr
                Front. Pediatr.
                Frontiers in Pediatrics
                Frontiers Media S.A.
                2296-2360
                08 May 2019
                2019
                : 7
                : 147
                Affiliations
                [1] 1Pediatric Unit, Department of Life Health and Environmental Sciences, University of L'Aquila , L'Aquila, Italy
                [2] 2Department of Pediatric, IRCCS San Raffaele Hospital , Milan, Italy
                [3] 3Pediatric Unit, Department of Biotechnology and Applied Sciences, University of L'Aquila , Aquila, Italy
                Author notes

                Edited by: Rodolfo A. Rey, Center for Endocrinology Research “Dr. César Bergadá”, Argentina

                Reviewed by: Lourdez Ibanez, Hospital Sant Joan de Déu Barcelona, Spain; George Paltoglou, National and Kapodistrian University of Athens Medical School, Greece

                *Correspondence: Giovanni Farello giovanni.farello@ 123456cc.univaq.it

                This article was submitted to Pediatric Endocrinology, a section of the journal Frontiers in Pediatrics

                Article
                10.3389/fped.2019.00147
                6519308
                31139600
                804aba4b-efe4-4e44-a5ad-804d10a5be87
                Copyright © 2019 Farello, Altieri, Cutini, Pozzobon and Verrotti.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 06 February 2019
                : 29 March 2019
                Page count
                Figures: 0, Tables: 1, Equations: 0, References: 75, Pages: 7, Words: 5968
                Categories
                Pediatrics
                Review

                puberty,pubarche,telarche,anticipation,development
                puberty, pubarche, telarche, anticipation, development

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